The present invention is concerned with new hypolipidemic compounds, with processes and novel intermediates for their preparation, with pharmaceutical compositions containing them and with their use in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions and associated conditions such as atherosclerosis.
Hyperlipidemic conditions are often associated with elevated plasma concentrations of low density lipoprotein (LDL) cholesterol. Such concentrations can be reduced by decreasing the absorption of bile acids from the intestine. One method by which this may be achieved is to inhibit the bile acid active uptake system in the terminal ileum. Such inhibition stimulates the conversion of cholesterol to bile acid by the liver and the resulting increase in demand for cholesterol produces a corresponding increase in the rate of clearance of LDL cholesterol from the blood plasma or serum.
The compounds of the present invention reduce the plasma or serum concentrations of LDL cholesterol and in consequence are particularly useful as hypolipidemic agents. By decreasing the concentrations of cholesterol and cholesterol ester in the plasma, the compounds of the present invention retard the build-up of atherosclerotic lesions and reduce the incidence of coronary heart disease-related events. The latter are defined as cardiac events associated with increased concentrations of cholesterol and cholesterol ester in the plasma or serum.
International Patent Application No. PCT/GB/9300328 describes 1,4-benzothiazepine compounds which have hypolipidemic activity. International Patent Application No. PCT/GB95/02700 (published as WO/9616051) describes 1,5-benzothiazepine compounds which also have hypolipidemic activity. A group of substituted 1,5-benzothiazepine compounds has been discovered which have surprising hypolipidemic activity over those specifically disclosed in the prior art.
Accordingly, the present invention provides a compound of formula (I) 
wherein
R1 is H or methyl; or a salt, solvate or physiologically functional derivative thereof.
Preferably R1 is hydrogen.
Suitable compounds of formula (I) are selected from:
(xc2x1)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide;
(3S)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-hydroxy-1,5-benzothiazepine-1,1-dioxide; and
(xc2x1)-2,3,4,5-Tetrahydro-3-ethyl-3-butyl-5-phenyl-7-chloro-8-methoxy-1,5-benzothiazepine-1,1-dioxide; or a salt, solvate or physiologically functional derivative thereof.
Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent, i.e., basic, compounds. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention include those derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulphonic and sulphuric acids, and organic acids, such as acetic, benzenesulphonic, benzoic, citric, ethanesulphonic, fumaric, gluconic, glycollic, isothionic, lactic, lactobionic, maleic, malic, methanesulphonic, succinic, p-toluenesulphonic, tartaric and trifluoroacetic acids. The chloride salt is particularly preferred for medical purposes. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, and alkaline earth salts, such as magnesium and calcium salts.
Salts having a non-pharmaceutically acceptable anion are within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, applications.
Any references to xe2x80x9ccompound(s) of formula (I)xe2x80x9d, xe2x80x9ccompounds of the present inventionxe2x80x9d, xe2x80x9ccompounds according to the inventionxe2x80x9d etc., refer to compound(s) of formula (I) as described above or their salts, solvates or physiologically functional derivatives as defined herein.
The term xe2x80x9cphysiologically functional derivativexe2x80x9d as used herein refers to any physiologically acceptable derivative of a compound of the present invention, for example, an ester, which upon administration to a mammal, such as a human, is capable of providing (directly or indirectly) such a compound or an active metabolite thereof. Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger""s Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: Principles And Practice.
Physiologically functional derivatives, which upon administration to a mammal, such as a human, is capable of providing (directly or indirectly) a compound of the invention or an active metabolite thereof, are commonly referred to as prodrugs. These prodrugs may or may not be active in their own right. Suitably, prodrugs of the present invention are formed at position R1 to give C1-6 ester or C1-6 alkoxy groups.
Active metabolites are those which may be generated in vivo by the metabolism of the compounds of the present invention and include, for example, glucuronides.
The compounds of the present invention can also exist in different polymorphic forms, for example, amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the present invention are within the scope of the invention and are a further aspect thereof.
The compounds of formula (I) are in forms wherein the carbon center xe2x80x94C(Et)(n-Bu)xe2x80x94 is chiral. The present invention includes within its scope each possible optical isomer substantially free, i.e. as associated with less than 5%, of any other optical isomer(s), and mixtures of one or more optical isomers in any proportions, including racemic mixtures. The (S)-isomer is preferred.
According to further aspects of the invention, there are also provided:
(a) the compounds of formula (I) and pharmaceutically acceptable salts, solvates and physiologically functional derivatives thereof for use as therapeutic agents, particularly in the prophylaxis and treatment of clinical conditions for which a bile acid uptake inhibitor is indicated, for example, a hyperlipidemic condition, and associated diseases such as atherosclerosis;
(b) pharmaceutical compositions comprising a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, or physiologically functional derivatives, at least one pharmaceutically acceptable carrier and, optionally, one or more other physiologically active agents;
(c) the use of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof in the manufacture of a medicament for the prophylaxis or treatment of a clinical condition for which a bile acid uptake inhibitor is indicated, for example, a hyperlipidemic condition, and associated diseases such as atherosclerosis;
(d) a method of inhibiting the absorption of bile acids from the intestine of a mammal, such as a human, which comprises administering an effective bile acid absorption inhibiting amount of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof to the mammal;
(e) a method of reducing the blood plasma or serum concentrations of LDL cholesterol in a mammal, such as a human, which comprises administering an effective cholesterol reducing amount of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof to the mammal;
(f) a method of reducing the concentrations of cholesterol and cholesterol ester in the blood plasma or serum of a mammal, such as a human, which comprises administering an effective cholesterol and cholesterol ester reducing amount of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof to the mammal;
(g) a method of increasing the fecal excretion of bile acids in a mammal, such as a human, which comprises administering an effective bile acid fecal excretion increasing amount of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof to the mammal;
(h) a method for the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a bile acid uptake inhibitor is indicated, for example, a hyperlipidemic condition, and associated diseases such as atherosclerosis, which comprises administering a therapeutically effective amount of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof to the mammal;
(i) a method of reducing the incidence of coronary heart disease-related events in a mammal, such as a human, which comprises administering an effective coronary heart disease-related events reducing amount of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof;
(j) a method of reducing the concentration of cholesterol in the blood plasma or serum of a mammal, such as a human, which comprises administering an effective cholesterol reducing amount of a compound of formula (I);
(k) processes for the preparation of compounds of formula (I) (including salts, solvates and physiologically functional derivatives thereof as defined herein); and
(l) novel chemical intermediates in the preparation of compounds of formula (I).
The compounds of the present invention may be administered conjunctively with other physiologically active agents, including hypolipidemic agents such as bile acid sequestering agents, fibric acid derivatives, or HMG-CoA reductase inhibitors (competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase), for example statins, such as pravastatin, lovastatin, fluvastatin, or simvastatin.
The amount of a compound of formula (I) which is required to achieve the desired biological effect will, of course, depend on a number of factors, for example, the specific compound chosen, the use for which it is intended, the mode of administration and the clinical condition of the recipient. In general, a daily dose is in the range of from 0.001 mg to 100 mg (typically from 0.01 mg to 50 mg) per day per kilogram bodyweight, for example, 0.01-10 mg/kg/day. Thus, orally administrable unit dose formulations, such as tablets or capsules, may contain, for example, from 0.1 to 100 mg, typically from 0.1 to 10 mg, preferably 0.1 to 5 mg. In the case of pharmaceutically acceptable salts, the weights indicated above refer to the weight of the benzothiazepine ion derived from the salt.
For the prophylaxis or treatment of the conditions referred to above, the compounds of formula (I) can be used as the compound per se, but are preferably presented with an acceptable carrier in the form of a pharmaceutical composition. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and must not be deleterious to the recipient. The carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compound. Other pharmacologically active substances can also be present including other compounds of formula (I). The pharmaceutical compositions of the invention can be prepared by any of the well known techniques of pharmacy consisting essentially of admixing the components.
When the compound of formula (I) is used in combination with one or more other physiologically active agents as described hereinbefore, the amount of the other physiologically active agents required to achieve the desired biological effect will also depend on a number of factors. The specific dose and dosing schedule will be readily determinable by those skilled in the art. In general, the dose utilized will be the dose approved for medical use in humans.
Pharmaceutical compositions according to the present invention include those suitable for oral, rectal, topical, buccal (e.g. sub-lingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular compound of formula (I) which is being used. Enteric-coated and enteric-coated controlled release formulations are also within the scope of the invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester. Suitable enteric coated and enteric coated controlled release formulations include tablets and capsules.
Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of formula (I); as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or moulding a powder or granules of the compound, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Moulded tablets can be made by moulding, in a suitable machine, the powdered compound moistened with an inert liquid diluent. Controlled release tablets can be prepared in similar manner and with the addition of, for example, hydroxypropylmethyl cellulose.
Enteric-coated tablets can be prepared by coating the tablets with an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer to prevent membrane cracking during application or on storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.
Enteric-coated controlled release tablets can be prepared by coating controlled release tablets with an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer to prevent membrane cracking during application or on storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.
Capsules can be prepared by admixing a compound of formula (I) with, for example, magnesium stearate, pregelantinised starch, sodium starch glycollate, and/or magnesium stearate and filling two-part hard gelatin capsules with the resulting mixture.
Controlled release capsule compositions can be prepared by admixing a compound of formula (I) with, for example, microcrystalline cellulose and/or lactose, extruding using an extruder, then spheronising and drying the extrudate. The dried pellets are coated with a release controlling membrane, for example ethyl cellulose, and filled into two-part, hard gelatin capsules.
Enteric capsule compositions can be prepared by admixing a compound of formula (I) with, for example, microcrystalline cellulose and/or lactose, extruding using an extruder, then spheronising and drying the extrudate. The dried pellets are coated with an enteric membrane, for example cellulose acetate phthalate containing a plasticizer, for example diethyl phthalate and filled into two-part, hard gelatin capsules.
Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of formula (I) in a flavored base, usually sucrose and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of formula (I), preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations can conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 5% w/w of the active compound.
Pharmaceutical compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound of formula (I) with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer. A suitable concentration of the active compound is about 1% to 35%, preferably about 3% to 15%. As one particular possibility, the active compound can be delivered from the patch by electrotransport or iontophoresis, for example, as described in Pharmaceutical Research, 3(6), 318 (1986).
The compounds of formula (I) can be prepared by conventional methods known to a skilled person or in an analogous manner to processes described in the art. For example, compounds of formula (I) wherein R1 is H can be prepared from compounds of formula (II) 
wherein R1a is an alkyl moiety (e.g., C1-4 alkyl, suitably methyl), by dealkylation with a suitable agent, such as boron tribromide, in a suitable organic solvent, for example methylene chloride.
According to a second process (B), a compound of formula (I) wherein R1 is methyl, or a salt, solvate, or physiologically functional derivative thereof, may be prepared from a compound of formula (III) 
by oxidation of the sulfur group with, for example, a mixture of osmium tetroxide and N-methyl-morpholine-N-oxide.
Compounds of formula (II) or (III) may be prepared from compounds of formula (IV), wherein R1a is defined above, by methods known in the art, particularly those described in WO96/16051. 
Compounds of formula (IV) can be prepared by methods described in WO96/16051 or by reacting compounds of formula (V) with compounds of formula (Va) 
wherein Z is a suitable leaving group, for example, halo, by first reacting the compound of formula (V) with a base, for example aqueous potassium hydroxide at an elevated temperature, for example 100xc2x0 C., cooling, and then adding the compound of formula (Va).
Compounds of formula (V) can be prepared from compounds of formula (VI) 
by reaction with ammonium thiocyanate and bromine in a suitable solvent such as acetic acid.
Compounds of formula (VI) are commercially available or can be prepared by methods well known or readily available to those skilled in the art.
Compounds of formula (Va) can be prepared from compounds of formula (VII) 
wherein R2 is a suitable hydroxy protecting group, for example, tert-butyldimethylsilyl, by oxidation of the compound of formula (VII) with, for example, sodium periodate and ruthenium trichloride in a suitable solvent such as carbon tetrachloride/acetonitrile/water. Subsequent to the oxidation, the R2 protected hydroxy is deprotected and converted to the appropriate leaving group Z by known methods, for example, with HBr.
Compounds of formula (VII) can be prepared from the corresponding diols by methods well known or readily available to those skilled in the art. The diols are commercially available or can be prepared by methods well known or readily available to those skilled in the art.
The compounds of formula (I), substantially free of other optical isomers can be obtained either by chiral synthesis, for example, by the use of the appropriate chiral starting material(s), such as a chiral compound of formula (Va), or by resolution of the products obtained from achiral syntheses, for example, by chiral hplc, enzymatic resolution, or by classical resolution with chiral acids.
Optional conversion of a compound of formula (I), or a compound of formula (I) comprising a basic substituent, to a corresponding acid addition salt may be effected by reaction with a solution of the appropriate acid, for example, one of those recited earlier. Optional conversion of a compound of formula (I) comprising an acidic substituent to a corresponding base salt may be effected by reaction with a solution of the appropriate base, for example, sodium hydroxide. Optional conversion to a physiologically functional derivative, such as an ester, can be carried out by methods known to those skilled in the art or obtainable from the chemical literature.
In addition, compounds of the formula (I) may be converted to different compounds of the formula (I) by standard methods known or available from the literature to those skilled in the art, for example by methylation of a hydroxy group.
For a better understanding of the invention, the following Examples are given by way of illustration and are not to be construed in any way as limiting the scope of the invention.
General Procedures: Proton magnetic resonance spectra were recorded at 300 MHz. Mass spectra were recorded under atmospheric pressure chemical ionization (APCI) conditions on a LCMS instrument or were performed by Oneida Research Services, Inc. under chemical ionization (CI) conditions using methane as the reagent gas. Elemental Analysis were performed by Atlantic Microlab, Inc. All reactions were performed under nitrogen atmosphere. TLC plates were Whatman MK6F silica gel 60 plates and were visualized under a UV lamp. Column chromatography was performed with EM Science silica Gel 60 (230-400 mesh). Reagents were obtained from Aldrich Chemical Co. unless otherwise noted and were used without further purification. Solvents were Aldrich anhydrous grade.